Phase 1 Trial of Neoadjuvant Radiation Therapy Before Prostatectomy for High-Risk Prostate Cancer

Duke Prostate Center, Duke Cancer Institute, Durham, North Carolina. Electronic address: .
International journal of radiation oncology, biology, physics (Impact Factor: 4.26). 06/2013; 87(1). DOI: 10.1016/j.ijrobp.2013.05.014
Source: PubMed
ABSTRACT
To evaluate, in a phase 1 study, the safety of neoadjuvant whole-pelvis radiation therapy (RT) administered immediately before radical prostatectomy in men with high-risk prostate cancer.
Twelve men enrolled and completed a phase 1 single-institution trial between 2006 and 2010. Eligibility required a previously untreated diagnosis of localized but high-risk prostate cancer. Median follow-up was 46 months (range, 14-74 months). Radiation therapy was dose-escalated in a 3 × 3 design with dose levels of 39.6, 45, 50.4, and 54 Gy. The pelvic lymph nodes were treated up to 45 Gy with any additional dose given to the prostate and seminal vesicles. Radical prostatectomy was performed 4-8 weeks after RT completion. Primary outcome measure was intraoperative and postoperative day-30 morbidity. Secondary measures included late morbidity and oncologic outcomes.
No intraoperative morbidity was seen. Chronic urinary grade 2+ toxicity occurred in 42%; 2 patients (17%) developed a symptomatic urethral stricture requiring dilation. Two-year actuarial biochemical recurrence-free survival was 67% (95% confidence interval 34%-86%). Patients with pT3 or positive surgical margin treated with neoadjuvant RT had a trend for improved biochemical recurrence-free survival compared with a historical cohort with similar adverse factors.
Neoadjuvant RT is feasible with moderate urinary morbidity. However, oncologic outcomes do not seem to be substantially different from those with selective postoperative RT. If this multimodal approach is further evaluated in a phase 2 setting, 54 Gy should be used in combination with neoadjuvant androgen deprivation therapy to improve biochemical outcomes.

Full-text

Available from: Judd W Moul, Mar 05, 2014
Clinical Investigation: Genitourinary Cancer
Phase 1 Trial of Neoadjuvant Radiation Therapy Before
Prostatectomy for High-Risk Prostate Cancer
Bridget F. Koontz, MD,
*
,z
Brian P. Quaranta, MD,
k
John A. Pura, MPH,
x
W.R. Lee, MD,
MEd,
*
,z
Zeljko Vujaskovic, MD, PhD,
*
,z
Leah Gerber, MS,
z
Michael Haake, MD,
{
Mitchell S. Anscher, MD,
#
Cary N. Robertson, MD,
y,z
Thomas J. Polascik, MD,
y,z
and Judd W. Moul, MD
y,z
*Department of Radiation Oncology,
y
Department of Surgery,
z
Duke Prostate Center, and
x
Division of Biostatistics, Duke
Cancer Institute, Durham, North Carolina;
k
21st Century Oncology, Asheville, North Carolina;
{
Southeast Radiation
Oncology, Charlotte, North Carolina; and
#
Department of Radiation Oncology, Virginia Commonwealth University,
Richmond, Virginia
Received Nov 28, 2012, and in revised form Apr 28, 2013. Accepted for publication May 5, 2013
Summary
This was a phase 1 study of
men with high-risk prostate
cancer, escalating preopera-
tive radiation dose followed
by prostatectomy within 8
weeks. Preoperative RT was
very well tolerated, although
postoperative incontinence
and stricture rates were rela-
tively high (33% and 17%,
respectively). Two-year
biochemical disease-free
survival was 67% in all
patients.
Purpose: To evaluate, in a phase 1 study, the safety of neoadjuvant whole-pelvis radiation therapy
(RT) administered immediately before radical prostatectomy in men with high-risk prostate cancer.
Methods and Materials: Twelve men enrolled and completed a phase 1 single-institution trial
between 2006 and 2010. Eligibility required a previously untreated diagnosis of localized but
high-risk prostate cancer. Median follow-up was 46 months (range, 14-74 months). Radiation
therapy was dose-escalated in a 3 3 design with dose levels of 39.6, 45, 50.4, and 54 Gy. The
pelvic lymph nodes were treated up to 45 Gy with any additional dose given to the prostate and
seminal vesicles. Radical prostatectomy was performed 4-8 weeks after RT completion. Primary
outcome measure was intraoperative and postoperative day-30 morbidity. Secondary measures
included late morbidity and oncologic outcomes.
Results: No intraoperative morbidity was seen. Chronic urinary grade 2þ toxicity occurred in 42%;
2 patients (17%) developed a symptomatic urethral stricture requiring dilation. Two-year actuarial
biochemical recurrence-free survival was 67% (95% confidence interval 34%-86%). Patients with
pT3 or positive surgical margin treated with neoadjuvant RT had a trend for improved biochemical
recurrence-free survival compared with a historical cohort with similar adverse factors.
Conclusions: Neoadjuvan t RT is feasible with moderate urinary morbidity . Howev er , oncologic
outcomes do not seem to be substantially different from those with selectiv e posto perati v e RT. If this
multimodal approach is further ev aluated in a phase 2 setting, 54 Gy should be used in combination with
neoadjuv ant androgen depriva tion therapy to improve biochemical outcomes. Ó 2013 Else vier Inc.
Reprint requests to: Bridget Koontz, MD, Duke University Medical
Center, Department of Radiation Oncology, DUMC Box 3085, Durham,
NC 27710.Tel: (919) 668-5213; E-mail: Bridget.Koontz@duke.edu
Presented in part at the American Society for Clinical Oncology
Genitourinary Symposium, February 2009; American Urological Associ-
ation Annual Meeting, Chicago IL April 25-30, 2009; and at the 53rd
Annual Meeting of the American Society for Radiation Oncology Annual
Meeting, Miami Beach, FL, October 2-6, 2011.
C.N.R., T .J.P. , and J.W.M. have receiv ed research support from the Com-
mittee for Urologic Research, Education, and Dev elopment at Duke Univ ersity.
B.F.K. had full access to all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data analysis.
Conflict of interest: none.
AcknowledgmentdThe authors thank Madeline Carroll, MS, Research
Manager, for her extensive efforts to ensure the success of this trial and
safety of its patients.
Int J Radiation Oncol Biol Phys, Vol. 87, No. 1, pp. 88e93, 2013
0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2013.05.014
Radiation Oncology
International Journal of
biology physics
www.redjournal.org
Page 1
Introduction
The combination of surgery and radiation therapy (RT) is
becoming more accepted for patients with locally advanced
prostate cancer. Several phase 3 clinical trials have now been
published showing an advantage to adjuvant RT after radical
prostatectomy (RP) for patients with high-risk features (1-3).In
other malignancies the treatment strategy progression from
surgery alone to postoperative RT to preoperative RT has resulted
in improved oncologic outcomes, primarily local control. This is
best illustrated in rectal cancer, for which initial studies comparing
surgery with adjuvant RT showed significant improvement in local
control (4) and later investigations of RT timing showed further
benefit to local control with preoperative compared with post-
operative RT (5). This benefit may be due to improved targeting
and/or better oxygenation in the preoperative setting.
An additional benefit of delivering treatment before surgery
may be the ability to reduce the total radiation dose and/or field
size. For example, a randomized trial in sarcoma patients
demonstrated similar local control and improved overall survival
with preoperative 50 Gy versus postoperative 66 Gy (6).An
update of that study in 2005 (7) demonstrated that patients treated
preoperatively had reduced rates of long-term symptomatic
fibrosis, an effect attributed to the higher dose and larger field size
required in the postoperative setting.
It is reasonable to hypothesize that similar benefits may be
seen for prostate cancer patients if RT is delivered before surgery.
Postoperative treatment requires high total doses (60þ Gy). In the
neoadjuvant setting, with a better-oxygenated environment, the
dose necessary to clear extraprostatic disease may be lower.
Additionally, anatomic changes that result from the removal of the
prostate (ie, the collapse of the bladder and rectum into the
prostatic fossa) create a scenario in which the volumes of bladder
and rectum receiving significant dose are higher than in cases in
which the prostate is intact. Thus neoadjuvant RT may reduce
damage to critical surrounding tissues by lowering both the total
dose and the percentage of the dose delivered to those structures.
However, because salvage RP has traditionally been well-known
to be associated with significant morbidity (8), use of RT before RP
even as a planned multimodal treatment is rare (9-11). Therefore in
2005 we designed a phase 1 trial to evaluate the safety of
neoadjuvant RT for prostate cancer. We report the results herein.
Methods and Materials
From May 2006 through January 2010 13 patients were enrolled
in this phase 1 dose escalation trial. Eligibility required a diag-
nosis of high-risk prostate cancer, defined as (1) prostate-specific
antigen (PSA) level 20 ng/mL, (2) Gleason score (GS) 8, (3)
clinical T3 disease, or (4) 2 of the following: PSA 10-19.9 ng/mL,
GS 7, clinical T2b-T2c. All staging studies (minimum of bone
scan and chest x-ray) must have been negative for metastatic
disease. The majority of patients (85%) also underwent CT and/or
MRI staging. Patients must have had a Karnofsky performance
status 80 and been considered appropriate surgical candidates by
their urologist. Age of 70 years or greater was initially an
exclusion criteria but was removed in 2009 as practice patterns
changed. Other exclusion criteria were any prior pelvic RT and
any androgen deprivation therapy (ADT) or chemotherapy, as well
as previous invasive malignancy other than nonmelanoma skin
cancer. One patient received RT at a local facility; all patients
underwent RP at the primary institution. The protocol was
approved by the institutional review board before activation and
underwent yearly review and renewal. The trial was registered on
ClinicalTrials.gov as trial identifier NCT01041326.
The study was designed as a 3 3 dose escalation trial, with
toxicity review 1 month after each cohort had completed RP. Four
radiation dose levels were planned: 39.6 Gy, 45 Gy, 50.4 Gy, and
54 Gy, with 3 patients in each level. Radical prostatectomy was
scheduled between 4 and 8 weeks from RT completion. Follow-up
was scheduled 1 month after RP, every 3 months for years 1-2,
every 6 months for years 3-4, and annually thereafter.
Both 3-dimensional conformal RT and intensity modulated RT
were allowed. Computed tomography and MRI were used for
planning. Fiducial markers were not used, to prevent scarring of
the rectoprostatic fascia. The initial 2 dose levels treated whole
pelvis, whereas in the latter 2 a prostate/seminal vesicles boost
was added after reaching 45 Gy. The superior border of the whole-
pelvis field extended to the L5-S1 interspace. Minimum inverse
planning constraints for critical organs were as follows: rectum
(V40 Gy <50%, V50 Gy <25%), bladder (V40 Gy <50%),
femoral heads (maximum dose 50 Gy), and small bowel (V45 Gy
<150 cm
3
). All plans were reviewed by an independent study
investigator to ensure therapy met protocol guidelines before start
of treatment. Radiation therapy was delivered in 5 1.8-Gy
fractions per week. All patients underwent open radical retro-
pubic prostatectomy with limited nodal dissection, as per standard
clinical practice at our institution. One patient had a unilateral
nerve-sparing procedure (patient 3), whereas the remainder did
not undergo nerve-sparing procedures.
Primary outcome measure was intraoperative and postoperative
day-30 morbidity. Secondary measures included late morbidity
and oncologic outcomes. Toxicity was scored by Common
Toxicity Criteria for Adverse Events, version 3, and the Clavien
classification for surgical complications (12). Incontinence was
defined from patient history as occasional stress incontinence
(grade 1), spontaneous requiring pads (grade 2), or requiring
intervention (grade 3). Dose-limiting toxicity (DLT) was defined
as (1) any grade 4þ toxicity, (2) any grade 3 toxicity except
urinary incontinence, medication-responsive diarrhea, or blood
transfusion, (3) grade 2þ fistula or fecal incontinence, or (4) any
grade intraoperative rectal injury. Escalation rules stipulated that
escalation to the next dose level would occur if no DLT occurred
in 3 consecutive patients. If 1 DLT occurred, an additional 3
patients would be enrolled at that dose level, and if 2 or more DLT
occurred, escalation would be stopped. Patients were followed for
toxicity even if determined to have biochemical recurrence.
Late morbidity was also evaluated using patient-completed
questionnaires, including the International Index of Erectile Func-
tion (potency) and International Prostate Symptom Score (urinary
symptoms). Biochemical failure was defined as a sustained post-
operative PSA level >0.2 ng/mL or initiation of postoperative
salvage treatmentincluding androgen deprivation. The percentage of
cancer involvement in biopsy cores versus surgical specimen was
compared. Percent involvement on biopsy was calculated by
dividing the sum length of cancer in each involved core (mm) by the
sum length of all cores. This method was validated in a population of
158 prostatectomy patients (intraclass coefficeint Z 0.425; P<.001).
All statistical analysis was performed using JMP, version 9.0,
and SAS, version 9.3, software (SAS Institute, Cary, NC).
Difference in the means of cancer volume from biopsy to
RP in patients with neoadjuvant RT was performed by 2-sided
Volume 87 Number 1 2013 Neoadjuvant radiation for prostate cancer 89
Page 2
matched-pair analysis. Actuarial biochemical recurrence-free
survival (BRFS) with 95% confidence interval (CI) was
calculated using the Kaplan-Meier method. For matched cohort
analysis of postoperative outcome, controls (no neoadjuvant RT
patients; 1 had adjuvant RT and 15 had salvage RT) were
retrospectively selected from 3291 patients who underwent RP at
the institution during the same time period who had similar risk
categories for clinical T stage, biopsy GS, and PSA level at
diagnosis, with blinding to pathologic results. A 3:1 matching
design was utilized using propensity score matching, for
a matched cohort of 35 controls (1 control was matched to 2
different cases) and the 12 study cases.
The logerank test was used to assess differences in survival
curves among cases and controls. Comparison of positive surgical
margin (PSM), extracapsular extension (ECE), and seminal
vesicle invasion proportions between cases and controls was
performed using
c
2
analyses, adjusting for each 3:1 matched set;
matched odds ratios and corresponding 95% CIs were estimated.
Difference in postoperative PSA level between cases and controls
was assessed using nonparametric, stratified Wilcoxon ranked
scores to account for the skewed nature of the PSA measurement
and the matched design.
Results
Patients and treatment characteristics
Thirteen patients enrolled and completed neoadjuvant RT. One
patient was diagnosed after RT with an anaplastic astrocytoma of
the brain and did not undergo RP; all other patients completed the
planned course of treatment. All patients except 1 received
intensity modulated RT. All patients underwent an open retropubic
procedure, and all but 1 had a non-nerve-sparing technique.
Between 2 and 12 nodes were dissected, with a median of 4.
Median delay between the last day of RT and RP was 6.3 weeks
(range, 4.0-6.9 weeks). Median follow-up was 46 months (range,
14-74 months).
Clinical and pathologic characteristics are described in Table 1.
Median age was 63 years (range, 47-72 years). At RP, 1 patient
was found to have node-positive disease. Eight patients (67%) had
an undetectable postoperative PSA level. The majority of patients
(58%) had disease extending outside of the prostate. Five patients
(42%) had microscopically positive surgical margins.
Neoadjuvant, intraoperative, and postoperative
day-30 morbidity
Acute toxicity during RT was minimal. Seven patients (54%)
developed grade 1 gastrointestinal toxicity. Eight patients (62%)
developed grade 1 genitourinary toxicity. There were no higher-
grade toxicities associated with RT. There was no significant intra-
operative morbidity. Median anesthesia time was 4 hours (range,
2.5-5 hours). Median blood loss was 800 mL (range, 200-1600 mL).
Median length of hospitalization was 1.8 days (range, 0.9-2.6 days).
Postoperatively, 1 patient developed a symptomatic lymphocele on
postoperative day 18 requiring CT-guided drainage (Clavien grade
IIIa). One patient failed a postoperative day 14 voiding trial but
passed on postoperative day 20. No patient had a DLT.
Late morbidity
Late morbidity is described in Table 2. No patient developed
a gastrointestinal toxicity. Occasional stress incontinence was
common (58%). Of the 4 patients who had persistent grade
2/3 incontinence, 1 did so only after instrumentation for
Table 1 Clinical and pathologic characteristics of patients completing protocol
Patient no. Dose (Gy) Age (y)
T stage
pN
Gleason
score PSA (ng/mL)
Percent
involvement
PSM
PSA outcome
(ng/mL)Clinical Pathologic Biopsy RP Dx Post-Op Biopsy RP
1 39.6 63 2a 2c N0 9 9 11.9 <0.1 19 4 N 0.1
2 39.6 63 2b 3a N0 9 9 5.1 <0.1 57 30 Y 0
3 39.6 61 2a 2c N0 8 8 6.4 <0.1 10 1 N >0.2
4 45.0 55 2a 2c N0 9 8 7.5 0.1 30 10 N 0
5 45.0 64 2b 3a N0 8 8 29.0 0.2 15 20 N >0.2
6 45.0 55 2c 2c N0 7 9 41.5 <0.1 45 40 N >0.2
7 50.4 63 1c 3a N0 8 7 15.1 <0.1 11 15 Y 0
8 50.4 65 1c 2c N0 8 7 6.1 <0.1 2 5 N 0
10 50.4 66 2b 3b N0 8 9 2.4 0.1 3 12 Y >0.2
11 54.0 47 3 3b N1 9 7 58.0 7.3 86 50 Y ADT
12 54.0 55 2c 3b N0 9 9 8.1 <0.1 73 35 Y 0
13 54.0 72 2c 3a N0 9 9 7.5 <0.1 31 7 N 0
Abbreviations: ADT Z androgen deprivation therapy; Dx Z at diagnosis; N Z no; pN Z pathologic nodal stage; Post-Op Z first postoperative PSA;
PSA Z prostate-specific antigen level; PSM Z positive surgical margin; RP Z radical prostatectomy; Y Z yes.
Table 2 Late morbidity
Grade GI
GU
ED
*
Stricture Incontinence
0 12 (100) 10 (83) 1 (8) 0
1 0 0 6 (50) 3 (25)
2 0 2 (17) 4 (33) 6 (50)
3 0 0 1 (8) 1 (8)
Abbreviations: ED Z erectile dysfunction; GI Z gastrointestinal;
GU Z genitourinary.
Values are number (percentage).
* Two patients declined sexual history.
Koontz et al. International Journal of Radiation Oncology Biology Physics90
Page 3
nephrolithiasis. Symptomatic urethral stricture requiring dilatation
occurred in 17% of patients. One man developed gross hematuria
and on transurethral resection of bladder tumor was found to have
recurrent prostate cancer. Three of 10 patients had clinically
significant worsening of International Prostate Symptom Score,
with change scores of 4 points between pre-RT and 6-month
post-RP values (13). Postoperative erectile dysfunction was
universal.
Oncologic outcomes
A decrease in cancer volume was noted, from 32% (mean percent
positive cores) to 19% on RP specimen (PZ.02). Four patients
(33%) developed PSA failure, and 2 additional patients initiated
ADT. One of the patients who received immediate ADT after RP
had pathologically involved lymph nodes and a residual detectable
postoperative PSA level; his PSA has remained undetectable on
indefinite ADT and was counted as a failure. The second patient
had an undetectable PSA level postoperatively but was initiated on
6 months’ ADT at the urologist’s discretion. Two years later his
PSA remains undetectable without further ADT; he was not
considered a failure. Another man’s PSA rose to 0.3 ng/mL but
then declined and stabilized at 0.1 ng/mL without treatment; thus
he was not considered a failure. Three of the 4 patients with PSA
failure were in the first 2 dose groups.
Biochemical recurrence-free survival results are shown in
Figure 1. Actuarial 2-year BRFS was 67% (95% CI 34-86%).
Five-year BRFS was 44% (95% CI 15-71%). One patient has
developed metastatic disease, and all remain alive at last follow-up.
Patients with RT showed a nearly 30% reduction in odds of PSM,
ECE, and seminal vesicle invasion, after controlling for matching
(Table 3). Confidence intervals were wide, suggesting low precision
due to a small sample size. Mean postoperative PSA level was not
significantly different between cases and controls (PZ.544).
Subgroup analysis comparing with the matched RP-only
cohort was undertaken to better understand the potential role of
neoadjuvant RT in clearing microscopic disease. Patients with
a positive surgical margin who received neoadjuvant RT had
BRFS similar to those with negative margins (Fig. 2A): 2-year
BRFS for historical controls with or without PSM were 62%
(95% CI 33%-81%) and 36% (95% CI 12%-61%), whereas 2-year
BRFS for neoadjuvant RT was 54% (95% CI 13%-83%) for
negative surgical margin and 60% (95% CI 13%-89%) for those
with PSM (PZ.391). A similar effect was noted when evaluated
by pT stage (Fig. 2B; PZ.123), with 2-year BRFS for control with
pT2 83% (95% CI 27%-97%), control with pT3 36% (95% CI
17%-56%), neoadjuvant RT with pT2 80% (95% CI 20%-97%),
and neoadjuvant RT with pT3 48% (95% CI 12%-77%).
Discussion
We report the nov el application of neoadjuvant R T as part of a multi-
disciplinary approach to high-risk prostate cancer . Most studies
comparing the safety of RP after RT have been done in the setting of
full-dose RT, with RP performed years later to salv age recurrent
disease. At that time, fibrosis of the periprostatic tissues increases the
technical difficulty and morbidity of the procedure (8). Before this trial
was initiated, only 1 protocol conducted in 1969 investigated
neoadjuv ant RT, concluding that it was indeed safe (9).Inthepast
3 years, a Canadian phase 1 trial giving 25 Gy in 5 fractions was
published, showing acceptable toxicity (10). A second protocol has
been presented using neoadjuvant 45 Gy and docetaxel, also showing
low toxicity to the combined approach (11). Our study varies from
these in that it used whole-pelvis radiation at standard fractionation.
Our study confirms that neoadjuvant RT is well tolerated, with
operative course and acute morbidity comparable to RP. Coelho
et al (14) reviewed 30 publications from large-volume urology
centers who reported perioperative and late urinary/sexual
morbidity, with a total of more than 39,000 patients who under-
went retropubic RP. Our perioperative outcomes compare
Fig. 1. Biochemical recurrence-free survival (BRFS) for all
patients (NZ12).
Table 3 Matched cohort analysis
Variable Controls (nZ35) Cases (nZ12) Odds ratio (95% CI) P
Positive surgical margin
Positive (%) 10.42 14.58 0.700 (0.178-2.756) .602
Extracapsular extension
Positive (%) 14.58 10.42 0.667 (0.193-2.307) .505
Seminal vesicle invasion
Positive (%) 6.25 18.75 0.667 (0.156-2.850) .532
Postoperative PSA level (ng/mL)
Mean (SD) 0.425 (0.916) 0.642 (2.098) - .544
Median (range) 0 (0-3.9) 0 (0-7.3) - -
Abbreviation: CI Z confidence interval. Other abbreviation as in Table 1.
Volume 87 Number 1 2013 Neoadjuvant radiation for prostate cancer 91
Page 4
favorably regarding operative time, blood loss, and length of
hospitalization.
Unfortunately, the late urinary morbidity rates in this study are
relatively high compared with RP patients, although they are
comparable to those receiving postoperative RT. We found that
67% had no or occasional stress incontinence not requiring pads
(grade 0-1). In a multicenter series of more than 1000 RP patients,
the patient-reported rate of incontinence requiring protection was
Fig. 2. (A) Kaplan-Meier curve of biochemical recurrence-free survival for matched controls and neoadjuvant radiation therapy (naRT)
cases, stratified by margin status. (B) Kaplan-Meier curve of biochemical recurrence-free survival for matched controls and neoadjuvant
radiation therapy (naRT) cases, stratified by pathologic T stage. Numbers of subjects at risk (alive with no recurrence) within each group are
shown in the table below the curves at 1-year intervals up to 5 years.
Koontz et al. International Journal of Radiation Oncology Biology Physics92
Page 5
33% (15), whereas European Organization for Research and
Treatment of Cancer study 22911 reported pad-free continence
rates of 56% at 3 months, increasing to 77% at 2 years (16). Our
symptomatic urethral stricture rate was 17% compared 18% for
patients receiving postoperative RT (2).
Regarding oncologic outcomes, downsizing of the tumor
burden was seen, although the relationship of this finding to
improved PSA control is unclear. A significant number of patients
still had positive margins. However, the presence of positive
margin after neoadjuvant RT may not correlate with residual
viable tumor, because prostate cancer has been shown to slowly
regress for up to 2 years after RT (17). This hypothesis is
supported by our comparison of historical cohorts with adverse
pathologic features of pathologic T3 disease and PSM.
Our final dose is lower than typically given after prostatectomy
but is well within the range of preoperative radiation doses that
have been found to be safe and effective in other settings. A dose
of 54 Gy was chosen to mimic preoperative prescriptions in rectal
cancer and sarcoma. In this combined-modality approach, the role
of the radiation was to sterilize microscopic disease in the
surrounding tissues, with the surgery being relied upon to
eliminate gross disease in the prostate itself. Doses in the
45-54 Gy range have proven effective at numerous other sites for
that purpose (5, 6) and are used in prostate cancer RT to sites of
anticipated subclinical disease (18).
This trial also reports reasonable biochemical control, although
the results fall short of the intervention arms of the postoperative
RT trials (1, 2). This outcome needs to be placed in the context of
the dose escalation design, with the starting dose only 39.6 Gy,
probably too low to effectively clear microscopic disease, and the
fact that all men were high risk according to GS and PSA level
before surgery. However, there are other important differences
between preoperative RT and postoperative RT that may skew
comparison. Postoperative margin status is known to be
a prognostic factor (19) and thus may be used in selecting patients
for postoperative RT that are most likely to succeed. With
neoadjuvant RT, clinical risk factors such as cT stage and presence
of ECE on preoperative MRI may help to select patients at highest
risk for adverse pathologic features and maximize potential benefit
of a future preoperative RT trial. Although a small subset of those
with prostate cancer, men requiring cystoprostatectomy may
benefit from neoadjuvant RT, given the additional bowel morbidity
limiting postoperative RT in these cases.
Androgen deprivation therapy does improve the results of RT
for high-grade prostate cancer (20). Two ongoing clinical trials,
Radiation Therapy Oncology Group protocol 0534 and
Radiotherapy and Androgen Depreviation In Combination After
Local Surgery (RADICALS) trial will provide insight as to the
role of adjuvant ADT combined with postoperative RT. We
suggest that if preoperative RT for high-risk patients is pursued,
a phase 2 evaluation of neoadjuvant RT should use 54 Gy, the
highest dose tested, and adjuvant hormonal therapy to provide
direct comparison with these other studies.
Conclusions
Neoadjuvant RT followed by immediate RP is safe and leads to
urinary morbidity comparable to that with postoperative RT. If this
multimodal approach is further evaluated in a phase 2 setting, it
should be done in combination with neoadjuvant ADT to improve
biochemical outcomes.
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